Adipose tissue promotes a serum cytokine profile related to lower insulin sensitivity after chronic central leptin infusion

Obesity is an inflammatory state characterized by an augment in circulating inflammatory factors. Leptin may modulate the synthesis of these factors by white adipose tissue decreasing insulin sensitivity. We have examined the effect of chronic central administration of leptin on circulating levels of cytokines and the possible relationship with cytokine expression and protein content as well as with leptin and insulin signaling in subcutaneous and visceral adipose tissues. In addition, we analyzed the possible correlation between circulating levels of cytokines and peripheral insulin resistance. We studied 18 male Wistar rats divided into controls (C), those treated icv for 14 days with a daily dose of 12 μg of leptin (L) and a pair-fed group (PF) that received the same food amount consumed by the leptin group. Serum leptin and insulin were measured by ELISA, mRNA levels of interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4, IL-6, IL-10 and tumor necrosis factor-α (TNF-α) by real time PCR and serum and adipose tissue levels of these cytokines by multiplexed bead immunoassay. Serum leptin, IL-2, IL-4, IFN-γ and HOMA-IR were increased in L and TNF-α was decreased in PF and L. Serum leptin and IL-2 levels correlate positively with HOMA-IR index and negatively with serum glucose levels during an ip insulin tolerance test. In L, an increase in mRNA levels of IL-2 was found in both adipose depots and IFN-γ only in visceral tissue. Activation of leptin signaling was increased and insulin signaling decreased in subcutaneous fat of L. In conclusion, leptin mediates the production of inflammatory cytokines by adipose tissue independent of its effects on food intake, decreasing insulin sensitivityThis work was supported by grants from Fondo de Investigación Sanitaria (PI10/0747), Ministerio de Ciencia y Tecnología (SAF 2010-22277), CIBERobn (CB03/06) and Fundación Endocrinología y Nutrición. S.C. is supported by CIBERob

Improvement in glycemia after glucose or insulin overload in leptin-infused rats is associated with insulin-related activation of hepatic glucose metabolism

Background: Insulin regulates glucose homeostasis through direct effects on the liver, among other organs, with leptin modulating insulin's hepatic actions. Since central leptin may modify insulin signaling in the liver, we hypothesized that leptin infusion activates hepatic glycogen synthesis following peripheral administration of a bolus of glucose or insulin, thus regulating glycemia. Findings: Oral glucose and intraperitoneal insulin tolerance tests were performed in control, intracerebroventricular leptin-treated and pair-fed rats during 14 days. An improvement in glycemia and an increase in hepatic free glucose and glycogen concentrations after glucose or insulin overload were observed in leptin-treated rats. In order to analyze whether the liver was involved in these changes, we studied activation of insulin signaling by Western blotting and multiplex bead immunoassay after leptin infusion. Our studies revealed an increase in phosphorylation of insulin receptor substrate-1 and Akt in leptin-treated rats. Examination of parameters related to glucose uptake and metabolism in the liver revealed an augment in glucose transporter 2 and a decrease in phosphoenolpyruvate carboxylase protein levels in this group. Conclusions: These results indicate that central leptin increases hepatic insulin signaling, associated with increased glycogen concentrations after glucose or insulin overload, leading to an improvement in glycemia.This work was supported by the Spanish Ministry of Science and Innovation with the help of European FEDER funding (FIS PI13/02195), Ministerio de Ciencia e Innovación (BFU2011-27492 and BFU2014-51836-C2-2-R), the Network Center for Biomedical Research on Obesity and Nutrition (CIBEROBN) Instituto Carlos III and Fundación Endocrinología y Nutrición. S.C. is supported by CIBEROB

Olive oil and wine as source of multi-target agents in the prevention of Alzheimer disease

Olive oil and wine are consumed daily worldwide and they constitute the fundamental pillars of the healthy Mediterranean diet. Polyphenolic compounds, naturally present in both olive oil and wine, are responsible for their beneficial properties. Current studies have shown the neuroprotective effects of polyphenols independently of their wellknown antioxidant action. In this work, we have focused on reviewing the protective effect of polyphenols from extra virgin olive oil and wine in Alzheimer´s disease (AD), to emphasize that both food could be a possible therapeutic tool. Beneficial effects have been described in β-aggregation, neurofibrillary tangles, autophagy and mitochondrial function, as well as in cerebral insulin resistance. Furthermore, to date a harmful dose has not been described. Both preclinical and clinical works demonstrate that polyphenols act on neuropathological and cognitive disorders of AD, preventing or stopping the onset of this devastating disease. However, there are certain limitations in these studies, since it is very difficult to research diseases that lead to cognitive impairment. Although all the findings obtained are very encouraging, more studies should be carried out to use the polyphenols from olive oil and wine as therapeutic agents in the progression of AD. Therefore, more longitudinal studies in humans with a homogeneous cohort of patients are necessary to corroborate the efficacy of these nutraceuticals, as well as analyze which is the most appropriate dose for this purpos

Could antibiotics be therapeutic agents in Alzheimer´s disease?

Alzheimer´s disease (AD) is an irreversible neurodegenerative disorder and one of the main aging-dependent maladies of the 21st century. Around 46 million people suffer from AD worldwide and this is projected to double within the next 20 years. Due to the progressive aging of the population and the prediction of an increase in the incidence of this disease, AD constitutes a serious familial and social health problem. Therefore, it is necessary to find new therapeutic strategies which are aimed to prevent, delay the onset, slow the progression and/or improve the symptoms of AD. Currently, the research is focused on finding and identifying new drugs for achieving these goals. In this chapter of the book, we widely review the neuroprotective role that some antibiotics could play in AD, because these drugs reach the brain quickly and are relatively inexpensive. Likewise, we have found evidence in both in vitro and in vivo studies and also in some clinical trials. In summary, all the reviewed antibiotics exert neuroprotection because they act on the main pathophysiological features of AD. Nevertheless, it must be taken into account that a long-term treatment with antibiotics could cause adverse effects including antibiotic resistance. Thus, properly clinical trials should be carried out in order to corroborate benefits of these antibiotics in people with AD

Neuroprotective antibiotics in Alzheimer´s disease

Alzheimer´s disease (AD) is an irreversible neurodegenerative disorder and one of the main agingdependent maladies of the 21st century. Currently, around 46 million people suffer from AD worldwide and this is projected to double within the next 20 years. Due to the progressive aging of the population and the prediction of an increase in the incidence of this disease, AD constitutes a serious familial and social health problem. Therefore, it is essential to find therapeutic strategies which are aim to prevent, delay the onset, slow the progression and/or improve the symptoms of AD. Nowadays, the research is focused on finding and identifying new drugs for achieving these goals. In this article we have focused on a thorough review of the neuroprotective role the antibiotics rifampicin, rapamycin and minocycline play in the treatment of AD as these medications reach the brain quickly and are relatively inexpensive. Likewise, we have found evidence in both “in vitro” and “in vivo” studies and also some clinical trials. In an overview, all the reviewed antibiotics exert neuroprotection because they act as anti-inflammatory and anti-amyloidogenic agent

Hydroxytyrosol improves mitochondrial energetics of a cellular model of Alzheimer’s disease

Mitochondrial energetic deficit is one of the hallmarks of neurodegenerative disorders, e.g. Alzheimer´s disease (AD). Adherence to a Mediterranean diet is associated with lower incidence of cognitive decline and AD and extra virgin olive oil’s (poly)phenols such as oleuropein and hydroxytyrosol (HT) are being actively studied in this respect. In this study, we assessed the effects of HT on mitochondrial energetic dysfunction in the 7PA2 cells cellular model, i.e. one of the best cellular models of Aβ toxicity with a well-characterized mitochondrial dysfunction typically observed in AD. We report an increase of new mitochondria at 8 h post HT-treatment, which was followed by higher mitochondrial fusion. Further, ATP concentrations were significantly increased after 24 h of treatment with HT as compared with controls. Our data suggest that HT may revert the energetic deficit of a cellular model of AD by potentiating mitochondrial activity. Because HT is being proposed as dietary supplement or component of functional foods, future studies in appropriate animal models and – eventually – humans are warranted to further investigate its potential neuroprotective actions in AD

Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model

Insulin receptor substrate-2-deficient (IRS2-/-) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2-/- mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2-/- mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2-/- mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, nondiabetic IRS2-/- mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamusThis work was supported by the Ministerio de Ciencia e Innovación [BFU2011- 27492 and BFU2014-51836-C2-2-R to J.A.C.; and SAF2012-33283 to A.M.V.]; Fondo de Investigación Sanitaria [PI1302195 to J.A.]; Centro de Investigación Biomédica en Red de Fisiopatologı́a de Obesidad y Nutrición (CIBEROBN); and Centro de Investigación Biomédica en Red Diabetes y Enfermedades asociadas (CIBERDEM), Instituto de Salud Carlos III, and Fundación de Endocrinologı́a y Nutrición